WO2022159835A1 - Inhibiteurs de nek7 - Google Patents

Inhibiteurs de nek7 Download PDF

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Publication number
WO2022159835A1
WO2022159835A1 PCT/US2022/013557 US2022013557W WO2022159835A1 WO 2022159835 A1 WO2022159835 A1 WO 2022159835A1 US 2022013557 W US2022013557 W US 2022013557W WO 2022159835 A1 WO2022159835 A1 WO 2022159835A1
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compound
mmol
alkyl
compounds
pyrrolo
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PCT/US2022/013557
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English (en)
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Alexis Henri Abel Mollard
David J. Bearss
John Sai Keong KAUWE III
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Halia Therapeutics, Inc.
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Publication of WO2022159835A1 publication Critical patent/WO2022159835A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Embodiments of the present disclosure are generally directed to compounds and methods for their preparation and use as therapeutic or prophylactic agents, for example for treatment of inflammation.
  • Inflammasomes are multi-protein complexes whose activation plays a central role in innate immunity and inflammation.
  • four inflammasomes have been described: NLRP1 , NLRC4, NLRP3, and AIM2.
  • the NLRP3 inflammasome is composed of NLRP3, ASC, and caspase-1. Its activation results in the activation of caspase- 1 which promotes the secretion of IL-ip and IL- 18, cytokines that mediate inflammation in animal disease models of several autoimmune diseases, myocardial infarction, metabolic syndromes, inflammatory bowel disease, and macrophage activation syndrome.
  • NEK7 is a member of the family of NIMA-related kinases (NEKs) that act as NLRP3 -binding proteins to regulate its oligomerization and activation.
  • NEK7 is a serine/threonine kinase essential for mitotic entry, cell cycle progression, cell division, and mitotic progression. It is expressed in a variety of tissues such as the brain, heart, lung, liver, and spleen. Overexpression of NEK7 induces the production of abnormal cells, which has an intimate connection to tumors, such as retinoblastoma, gallbladder cancer and carcinoma of the head and neck.
  • Inhibitors of NLRP3 inflammasome activation that block the NLRP3-NEK7 interaction can have therapeutic or prophylactic activity in several human diseases, such as type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases.
  • T2D type 2 diabetes
  • atherosclerosis a great number of inhibitors have been widely used to disturb effector signaling pathways, involving IL-ip or IL- 18 without abolishing the inflammation response.
  • Inhibitors of NLRP3 inflammasome activation that block the NLRP3-NEK7 interaction can have therapeutic or prophylactic activity in several human diseases, such as type 2 diabetes (T2D), atherosclerosis, gout, and neurodegenerative diseases.
  • T2D type 2 diabetes
  • atherosclerosis a gout
  • embodiments of the present disclosure provide compounds, including pharmaceutically acceptable salts, stereoisomers, and prodrugs thereof, which are capable of modulating the activity of the NLRP3 inflammasome.
  • One embodiment provides compounds of Structure (I): or pharmaceutically acceptable salts, stereoisomers or prodrug thereof, wherein each of A, X, Y, Z, R la , R lb , R 2a , R 2b , R 3 , and R 4 are as defined herein.
  • compositions comprising the disclosed compounds, and methods of use of the same for treatment of inflammation are also provided.
  • any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • the terms “about” and “approximately” mean ⁇ 20%, ⁇ 10%, ⁇ 5%, or ⁇ 1% of the indicated range, value, or structure, unless otherwise indicated.
  • the terms “a” and “an” as used herein refer to “one or more" of the enumerated components.
  • the use of the alternative should be understood to mean either one, both, or any combination thereof of the alternatives.
  • Amino refers to the -NH2 radical.
  • Carboxy or “carboxyl” refers to the -CO2H radical.
  • Niro refers to the -NO2 radical.
  • “Alkyl” refers to a saturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (C 1 -C 8 alkyl) or one to six carbon atoms (C 1 -C 6 alkyl), or any value within these ranges, such as C4-C6 alkyl and the like, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, zz-propyl, 1-methylethyl (iso-propyl), zz-butyl, zz-pentyl, 1,1 -dimethylethyl (/-butyl), 3 -methylhexyl, 2-methylhexyl and the like.
  • the number of carbons referred to relates to the carbon backbone and carbon
  • Alkenyl refers to an unsaturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds, having from two to twelve carbon atoms (C2-C12 alkenyl), two to eight carbon atoms (C 2 -C 8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl), or any value within these ranges, and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-l-enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.
  • the number of carbons referred to relates to the carbon backbone and carbon branching, but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted.
  • alkynyl refers to unsaturated straight or branched hydrocarbon radical, having 2 to 12 carbon atoms (C2-C12 alkynyl), two to nine carbon atoms (C2-C9 alkynyl), or two to six carbon atoms (C2-C6 alkynyl), or any value within these ranges, and having at least one carbon- carbon triple bond.
  • alkynyl groups may be selected from the group consisting of ethynyl, propargyl, but-1 -ynyl, but-2-ynyl and the like.
  • the number of carbons referred to relates to the carbon backbone and carbon branching, but does not include carbon atoms belonging to any substituents. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted.
  • Alkoxy refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above containing one to twelve carbon atoms (C1-C12 alkoxy), one to eight carbon atoms (C1-C8 alkoxy) or one to six carbon atoms (C1-C6 alkoxy), or any value within these ranges. Unless stated otherwise specifically in the specification, an alkoxy group is optionally substituted.
  • Aminyl refers to a radical of the formula -NRaRb, where R a and Rb are each independently H or C 1 -C 6 alkyl as defined above. When both of Ra and Rb are H, an “aminyl” group is the same as an “amino” group as defined above.
  • the Ci-Ce alkyl portion of an aminyl group is optionally substituted unless stated otherwise.
  • Aromatic ring refers to a cyclic planar molecule or portion of a molecule (i.e., a radical) with a ring of resonance bonds that exhibits increased stability relative to other connective arrangements with the same sets of atoms.
  • Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, pyrimidonyl. Unless stated otherwise specifically in the specification, an "aromatic ring" includes all radicals that are optionally substituted.
  • Aryl refers to a carbocyclic ring system radical comprising 6 to 18 carbon atoms, for example 6 to 10 carbon atoms (C 6 -C 10 aryl) and at least one carbocyclic aromatic ring.
  • the aryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, ⁇ .s-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl group is optionally substituted.
  • Carbocyclic or “carbocycle” refers to a ring system, wherein each of the ring atoms are carbon.
  • Cycloalkyl refers to a non-aromatic monocyclic or polycyclic carbocyclic radical consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen ring carbon atoms (C3-C15 cycloalkyl), from three to ten ring carbon atoms (C3-C10 cycloalkyl), or from three to eight ring carbon atoms (C 3 -C 8 cycloalkyl), or any value within these ranges such as three to four carbon atoms (C3-C4 cycloalkyl), and which is saturated or partially unsaturated and attached to the rest of the molecule by a single bond.
  • Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic radicals include, for example, adamantyl, norbomyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group is optionally substituted.
  • fused refers to any ring structure described herein which is fused to another ring structure.
  • Halo refers to bromo, chloro, fluoro, or iodo.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group is optionally substituted.
  • Halocycloalkyl refers to a cycloalkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a halocycloalkyl group is optionally substituted.
  • Hydroxylalkyl refers to an alkyl radical, as defined above that is substituted by one or more hydroxyl radical.
  • the hydroxylalkyl radical is joined at the main chain through the alkyl carbon atom. Unless stated otherwise specifically in the specification, a hydroxylalkyl group is optionally substituted.
  • Heterocyclyl refers to a 3- to 18-membered, for example 3- to 10-membered or 3- to 8-membered, non-aromatic ring radical having one to ten ring carbon atoms (e.g., two to ten) and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is partially or fully saturated and is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spirocychc and/or bridged ring systems.
  • Nitrogen, carbon and sulfur atoms in a heterocyclyl radical are optionally oxidized, and nitrogen atoms may be optionally quatemized.
  • heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, hexahydro- IH-pyrrolizine, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, azetidinyl, pyrrol
  • Heteroaryl refers to a 5- to 18-membered, for example 5- to 6-membered, ring system radical comprising one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • Heteroaryl radicals may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[Z>][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotri azolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiopheny
  • substituted means any of the above groups (e.g, alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl and/or hydroxylalkyl) wherein at least one hydrogen atom (e.g, 1, 2, 3 or all hydrogen atoms) is replaced by a bond to a non-hydrogen substituent.
  • groups e.g, alkyl, alkenyl, alkylene, alkylcarbonyl, alkoxy, alkoxyalkyl, aminylalkyl, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclene, heterocyclylalkyl, heteroaryl, heteroarylalkyl
  • non-hydrogen substituents include, but are not limited to: amino, carboxyl, cyano, hydroxyl, halo, nitro, oxo, thiol, thioxo, alkyl, alkenyl, alkylcarbonyl, alkoxy, aryl, cyanoalkyl, cycloalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and/or hydroxylalkyl substituents, each of which may also be optionally substituted with one or more of the above substituents.
  • the optional substitutions are independently selected from the group consisting of halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Cs-Cs cycloalkyl, Cs-Cs halocycloalkyl, Ce-Cio aryl, 5- or 6-membered heteroaryl, Ci-Ce alkoxy and 3-8 membered heterocyclyl.
  • an effective amount refers to that amount of a compound described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below.
  • the therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells, e.g., reduction of platelet adhesion and/or cell migration.
  • treatment or “treating” refer to an approach for obtaining beneficial or desired results with respect to a disease, disorder or medical condition including but not limited to a therapeutic effect and/or a prophylactic effect.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
  • a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
  • co-admini strati on encompass administration of two or more agents to an animal, including humans, so that both agents and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness of the free bases, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002.
  • Preferred pharmaceutically acceptable acid addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
  • Pharmaceutically acceptable acid addition salts which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness of the free acids, which are biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable base addition salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
  • Pharmaceutically acceptable base addition salts are prepared from addition of an inorganic base or an organic base to the free acid.
  • Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, A-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isoprop
  • pharmaceutically acceptable salts include quaternary ammonium salts such as quaternary amine alkyl halide salts (e.g., methyl bromide).
  • antagonists are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as NLRP3 inflammasome or NEK7 or the association of NLRP3 inflammasome - NEK7. Accordingly, the terms “antagonist” and “inhibitors” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.
  • agonist refers to a compound having the ability to initiate or enhance a biological function of a target protein, whether by inhibiting the activity or expression of the target protein. Accordingly, the term “agonist” is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance a biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.
  • Signal transduction is a process during which stimulatory or inhibitory signals are transmitted into and within a cell to elicit an intracellular response.
  • selective inhibition or “selectively inhibit” refers to a biologically active agent's ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.
  • Subject refers to an animal, such as a mammal, for example a human.
  • the methods described herein can be useful in both human therapeutics and veterinary applications.
  • the subject is a mammal, and in some embodiments, the subject is human.
  • “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., compounds of Structure (I)).
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs are also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or thiol group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • in vivo refers to an event that takes place in a subject’s body.
  • embodiments are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, embodiments include compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.
  • an animal such as rat, mouse, guinea pig, monkey, or to human
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • solvate refers to an aggregate that comprises one or more compounds of the disclosure with one or more molecules of solvent.
  • the solvent is water, in which case the solvate is a hydrate.
  • the solvent is an organic solvent.
  • the compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as the corresponding solvated forms.
  • the compounds of the disclosure are a true solvate, while in other cases, the compounds of the disclosure merely retain adventitious water or is a mixture of water plus some adventitious solvent.
  • "Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • a “pharmaceutical composition” refers to formulations of compounds of the disclosure and a medium generally accepted in the art for the delivery of compounds of the disclosure to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • the compounds of the disclosure may contain one or more centers of geometric asymmetry and may thus give rise to stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids.
  • stereoisomers such as enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids.
  • Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (5)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • Embodiments of the present disclosure include all manner of rotamers and conformationally restricted states of a compound of the disclosure.
  • Atropisomers which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included.
  • certain compounds of the disclosure may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.
  • the compounds of Structure (I) are a mixture of enantiomers or diastereomers. In other embodiments, the compounds of Structure (I) are substantially one enantiomer or diastereomer.
  • a “tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. Embodiments thus include tautomers of the disclosed compounds.
  • the chemical naming protocol and structure diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, using the ACD/Name Version 9.07 software program and/or ChemDraw Profesional Version 17.0.0.206 software naming program (CambridgeSoft).
  • a substituent group is typically named before the group to which it attaches.
  • cyclopropylethyl comprises an ethyl backbone with a cyclopropyl substituent.
  • all bonds are identified in the chemical structure diagrams herein, except for all bonds on some carbon atoms, which are assumed to be bonded to sufficient hydrogen atoms to complete the valency.
  • the disclosure provides compounds including pharmaceutically acceptable salts, stereoisomers and prodrugs thereof, which are capable of modulating the activity of the NLRP3 inflammasome.
  • Embodiments of the present disclosure provide a compound having the following Structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:
  • A is C 6 -Cio aryl, C3-C10 cycloalkyl, 3-10 membered heterocyclyl, or 5-6 membered monocyclic heteroaryl, each of which is optionally substituted with one or more R 5 ;
  • X is N or CR 1C ;
  • Y is N or CR ld ;
  • Z is C(R 6 )(R 7 ) or NR 6 ;
  • R la , R lb , R lc , and R ld are each independently H, halo, C 1 -C 6 alkyl, or C3-C8 cycloalkyl;
  • R 2a and R 2b are each independently H, halo, cyano, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C3-C8 cycloalkyl, or C3-C8 halocycloalkyl, provided that R 2a and R 2b are not both H;
  • R 3 is C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, heteroaryl, or aryl, each of which is optionally substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2- C 6 alkenyl, C2-C6 alkynyl, and C 1 -C 6 alkoxy;
  • R 4 is H, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, Ce-Cio aryl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one more substituents selected from halo, hydroxyl, cyano, aminyl, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 1 -C 6 alkoxy;
  • R 5 is, at each occurrence, independently halo, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C 1 -C 6 haloalkyl;
  • R 6 is H, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C 1 -C 6 hydroxylalkyl
  • R 7 is H, OH, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C 1 -C 6 hydroxylalkyl.
  • A is C 6 -C 10 aryl. In certain embodiments, A is C3-C10 cycloalkyl. In some specific embodiments, A is 3-10 membered heterocyclyl. In certain specific embodiments, A is 5-6 membered monocyclic heteroaryl. In some more specific embodiments, A is substituted with one or more occurrences of R 5 . In certain more specific embodiments, A is substituted with one or two occurrences of R 5 . In some embodiments, A is substituted with substituents selected from the group consisting of halo, C 1 -C 6 haloalkyl, and combinations thereof. In certain embodiments, A is substituted with substituents selected from the group consisting of fluoro, trifluoromethyl, and combinations thereof. In more specific embodiments, A is unsubstituted.
  • X is N. In certain embodiments, X is CR 1C . In some specific embodiments, R lc is H. In certain more specific embodiments, R lc is halo (e.g., R lc is chloro). In some other embodiments, R lc is C 1 -C 6 alkyl (e.g., R lc is methyl). In certain embodiments, R lc is C 3 -C 8 cycloalkyl (e.g., R lc is cyclopropyl).
  • Y is N. In other embodiments, Y is CR ld . In some embodiments, R ld is H. In certain specific embodiments, R ld is halo, Ci-Ce alkyl, or C3- Cs cycloalkyl.
  • Z is C(R 6 )(R 7 ).
  • R 6 is H.
  • R 7 is -OH, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C 1 -C 6 hydroxylalkyl. In certain specific embodiments, R 6 and R 7 are both H.
  • Z is NR 6 .
  • R 6 is H.
  • R 6 is C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C 1 -C 6 hydroxylalkyl.
  • R la is H. In some embodiments, R la is C 1 -C 6 alkyl (e.g., R la is methyl). In some embodiments, R la is halo or C3-C8 cycloalkyl.
  • R lb is H. In certain embodiments, R lb is halo, C 1 -C 6 alkyl, or C3-C8 cycloalkyl.
  • R 2a is C 1 -C 6 alkyl (e.g., R 2a is tert-butyl or methyl). In some embodiments, R 2a is C3-C8 cycloalkyl. In more specific embodiments, R 2a is cyclopropyl. In some embodiments, the cyclopropyl is unsubstituted. In some embodiments, the cyclopropyl is substituted with at least one haloalkyl (e.g., trifluoromethyl). In certain more specific embodiments, R 2a has the following structure:
  • R 2b is H. In certain embodiments, R 2b is halo, cyano, Ci- C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, C 3 -C 8 cycloalkyl, or C 3 -C 8 halocycloalkyl.
  • R 3 is Ci-Ce alkyl (e.g., R 3 is methyl).
  • R 3 is aryl.
  • R 3 is phenyl.
  • the phenyl is substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C 1 -C 6 alkoxy.
  • the phenyl is unsubstituted.
  • R 3 is 3-10 membered heterocyclyl.
  • R 3 is piperidinyl.
  • the piperidinyl is substituted with one or more substituents selected from halo, hydroxyl, cyano, aminyl, C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and Ci-Ce alkoxy.
  • R 3 has the following structure:
  • R 4 is H. In more specific embodiments, R 4 is Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3 -C 8 cycloalkyl, 3-8 membered heterocyclyl, Ce- C10 aryl, or 5- or 6-membered heteroaryl.
  • the compound of Structure (I) is a modulator of the NLRP3 inflammasome.
  • the compound of Structure (I) is an inhibitor of NEK7 in a patient or in a biological sample.
  • the compound has one of the structures set forth in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.
  • Compounds in Table 1 were prepared as described in the Examples or methods known in the art and analyzed by mass spectrometry and/or 1 H NMR.
  • Table 1 Representative compounds of Structure (I)
  • R lb , R 2a , R 2b , R 3 , R 4 , R 6 , and R 7 have the meanings described herein, illustrate examples of methods of making the compounds of Structure (I) where Z is C(R 6 )(R 7 ):
  • reaction of the appropriate pyrazole- amine and carboxylic acid in the presence of a coupling agent and a base yields alcohol Intermediate F which can be coupled with the halopyri(mi)dine of the bicyclic system of Intermediate A under palladium-catalyzed conditions to afford aryl ether
  • Suitable protecting groups include, but are not limited to, hydroxy, amino, mercapto and carboxylic acid.
  • Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, /-butyldimethylsilyl, /-butyldiphenylsilyl or trimethyl silyl), tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, amidino and guanidino include /-butoxy carbonyl, benzyloxycarbonyl, and the like.
  • Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or arylalkyl), /?-methoxybenzyl, trityl and the like.
  • Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters.
  • Protecting groups are optionally added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley.
  • the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.
  • compositions comprising any one (or more) of the foregoing compounds and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is formulated for oral administration.
  • the pharmaceutical composition is formulated for injection.
  • the pharmaceutical compositions comprise a compound as disclosed herein and an additional therapeutic agent (e.g., anticancer agent).
  • additional therapeutic agent e.g., anticancer agent
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
  • a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation.
  • long acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compound is delivered in a targeted drug delivery system, for example, in a liposome coated with and organ-specific antibody.
  • the liposomes are targeted to and taken up selectively by the organ.
  • the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
  • the compound described herein is administered topically.
  • an effective amount of at least one compound of Structure (I) is administered to a subject suffering from or diagnosed as having such a disease, disorder, or medical condition.
  • Effective amounts or doses may be ascertained by methods such as modeling, dose escalation studies or clinical trials, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • the compounds according to the disclosure are effective over a wide dosage range.
  • dosages from 10 to 5000 mg, from 100 to 5000 mg, from 1000 mg to 4000 mg per day, and from 1000 to 3000 mg per day are examples of dosages that are used in some embodiments.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • compounds of the disclosure are administered in a single dose.
  • such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly.
  • other routes are used as appropriate.
  • a single dose of a compound of the disclosure may also be used for treatment of an acute condition.
  • compounds of the disclosure are administered in multiple doses.
  • dosing is about once, twice, three times, four times, five times, six times, or more than six times per day.
  • dosing is about once a month, once every two weeks, once a week, or once every other day.
  • compounds of the disclosure and another agent e.g., anti-cancer agent
  • are administered together about once per day to about 6 times per day.
  • the administration of compounds of the disclosure and an agent continues for less than about 7 days.
  • the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • compounds of the disclosure may continue as long as necessary. In some embodiments, compounds of the disclosure are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, compounds of the disclosure are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, compounds of the disclosure are administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
  • the compounds of the disclosure are administered in individual dosage forms. It is known in the art that due to inter-subject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy.
  • the compounds described herein are formulated into pharmaceutical compositions.
  • pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the disclosed compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).
  • compositions comprising one or more compounds of Structure (I), and a pharmaceutically acceptable carrier.
  • compositions comprising one or more compounds selected from compounds of Structure (I) and pharmaceutically acceptable diluent(s), excipient(s), and carrier(s).
  • the compounds described are administered as pharmaceutical compositions in which one or more compounds selected from compounds of Structure (I) are mixed with other active ingredients, as in combination therapy.
  • the pharmaceutical compositions include one or more compounds of Structure (I).
  • compositions of the compounds of Structure (I) are modulators of the NLRP3 inflammasome.
  • compositions of the compounds of Structure (I) inhibit NEK7 when administered to a patient or a biological sample.
  • a pharmaceutical composition refers to a mixture of one or more compounds selected from compounds of Structure (I) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of one or more compounds selected from compounds of Structure (I) provided herein are administered in a pharmaceutical composition to a mammal having a disease, disorder or medical condition to be treated.
  • the mammal is a human.
  • therapeutically effective amounts vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • the compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.
  • one or more compounds selected from compounds of Structure (I) are formulated in aqueous solutions.
  • the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank’s solution, Ringer’s solution, or physiological saline buffer.
  • one or more compounds selected from compounds of Structure (I) are formulated for trans-mucosal administration.
  • trans-mucosal formulations include penetrants that are appropriate to the barrier to be permeated.
  • appropriate formulations include aqueous or non-aqueous solutions.
  • such solutions include physiologically compatible buffers and/or excipients.
  • compounds described herein are formulated for oral administration.
  • Compounds described herein are formulated by combining the active compounds with, e.g., pharmaceutically acceptable carriers or excipients.
  • the compounds described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.
  • pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.
  • disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or algimc acid or a salt thereof such as sodium alginate.
  • dosage forms such as dragee cores and tablets, are provided with one or more suitable coating.
  • concentrated sugar solutions are used for coating the dosage form.
  • the sugar solutions optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.
  • Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • push-fit capsules contain the active ingredients in admixture with one or more filler.
  • Fillers include, by way of example only, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • soft capsules contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol.
  • stabilizers are optionally added.
  • the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations.
  • the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles.
  • Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • suspensions of one or more compounds selected from compounds of Structure (I) are prepared as appropriate oily injection suspensions.
  • suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • compositions include at least one pharmaceutically acceptable carrier, diluent, or excipient, and one or more compounds selected from compounds of Structure (I), described herein as an active ingredient.
  • the active ingredient is in free- acid or free-base form, or in a pharmaceutically acceptable salt form.
  • the methods and pharmaceutical compositions described herein include the use of N- oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass un-solvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and/or other therapeutically valuable substances.
  • compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid.
  • Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
  • Semi-solid compositions include, but are not limited to, gels, suspensions and creams.
  • compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.
  • compositions comprising one or more compounds selected from compounds of Structure (I) illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically when the composition is administered as a suspension, a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix.
  • a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.
  • aqueous suspensions contain one or more polymers as suspending agents.
  • Polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers.
  • Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.
  • compositions also, optionally, include solubilizing agents to aid in the solubility of one or more compounds selected from compounds of Structure (I).
  • solubilizing agent generally includes agents that result in formation of a micellar solution or a true solution of the agent.
  • Certain acceptable nonionic surfactants for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.
  • compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
  • bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris- hydroxymethylaminomethane
  • buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • compositions optionally include one or more preservatives to inhibit microbial activity.
  • Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.
  • Compositions may include one or more surfactants to enhance physical stability or for other purposes.
  • Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.
  • Compositions may include one or more antioxidants to enhance chemical stability where required.
  • Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.
  • aqueous suspension compositions are packaged in single-dose non-reclosable containers.
  • multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.
  • hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, the compounds described herein are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are useful herein. In some embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.
  • the formulations described herein comprise one or more antioxidants, metal chelating agents, thiol containing compounds and/or other general stabilizing agents.
  • stabilizing agents include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
  • polysorbate 20 (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan poly sulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.
  • the concentration of one or more compounds selected from compounds of Structure (I) provided in the pharmaceutical compositions of the present disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25%
  • the concentration of one or more compounds selected from compounds of Structure (I) provided in the pharmaceutical compositions of the present disclosure is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40 %, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately
  • the amount the one or more compounds selected from compounds of Structure (I) provided in the pharmaceutical compositions of the present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02
  • the amount of the one or more compounds selected from compounds of Structure (I) provided in the pharmaceutical compositions of the present disclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.
  • Packaging materials for use in packaging pharmaceutical compositions described herein include those found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.
  • Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the container(s) includes one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein.
  • kits optionally have a sterile access port (for example the container is an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • kits optionally comprise a compound with an identifying description or label or instructions relating to its use in the methods described herein.
  • a kit typically includes one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein.
  • materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
  • a set of instructions will also typically be included.
  • a label is optionally on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself, a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application.
  • the label indicates directions for use of the contents, such as in the methods described herein.
  • the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein.
  • the pack for example contains metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration.
  • the pack or dispenser is accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration.
  • Such notice for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Embodiments of the present disclosure are useful as modulators of the NLRP3 inflammasome via the inhibition of NEK7 in a host species. Therefore, the compounds of Structure (I) are also useful in the treatment of conditions mediated by effector signaling molecules like IL- 10 and IL- 18.
  • the host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of human disease.
  • the present disclosure is useful as an inhibitor of the NLRP3 inflammasome activation mechanism. Therefore, the compounds of Structure (I) are also useful in the treatment of conditions resulting from that activation in a host species.
  • the compounds of Structure (I) are useful as inhibitors of the NLRP3 (protein) -NEK7 (protein) interaction. Therefore, the compounds are also useful in the treatment of conditions resulting from the association of NLRP3-NEK7 in a host species.
  • the compounds of Structure (I) are useful in treating human conditions mediated by effectors selected from the group consisting of IL- 10, IL- 18, and caspase- 1.
  • Embodiments of the disclosure also relate to the use of compounds according to Structure (I) and/or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or modulated by the NLRP3 inflammasome activity. Furthermore, embodiments of the disclosure relate to the use of compounds according to Structure (I) and/or physiologically acceptable salts thereof for the production of a medicament for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or modulated by NLRP3 inflammasome activity. In certain embodiments, the disclosure provides the use of a compound according to Structure I or physiologically acceptable salts thereof, for the production of a medicament for the prophylactic or therapeutic treatment of a NLRP3 -mediated disorder.
  • the present disclosure relates to a method of treating inflammatory diseases or conditions mediated by NLRP3 inflammasome by administering to a patient in need thereof a therapeutically effective amount of the compound of Structure (I).
  • the diseases which can be treated with a compound of Structure (I) include type II diabetes, atherosclerosis, Alzheimer’s disease, aging, fatty liver disease, metabolic syndrome, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, enteritis, hepatitis, peritonitis, silicosis, UV- induced skin sunburn, contact hypersensitivity, sepsis, cancer, myelodysplastic syndrome (MDS), neurodegenerative disease, multiple sclerosis, Muckle-Wells syndrome, and combinations thereof.
  • the compounds of Structure (I) are used in methods for treatment of disorders or diseases selected from auto-immune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergy, asthma, pancreatitis, multi -organ failure, kidney diseases, platelet aggregation, cancer, myelodysplastic syndrome (MDS), transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injuries, respiratory diseases, ischemic conditions, and combinations thereof.
  • disorders or diseases selected from auto-immune, inflammatory disorders, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergy, asthma, pancreatitis, multi -organ failure, kidney diseases, platelet aggregation, cancer, myelodysplastic syndrome (MDS), transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injuries, respiratory diseases, ischemic conditions, and combinations thereof.
  • the disorders associated with NEK7 which are treatable with a compound of Structure (I) are selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn’s Disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin associated periodic syndromes, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult's onset Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA ( Deficiency of IL-1 Receptor Antagonist), Alzheimer’s disease, Parkinson’s disease, cancer,
  • Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants and methotrexate.
  • NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, hydroxychloroquine, and combinations thereof.
  • NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib dnd/or etoricoxib.
  • the anti-inflammatory agent is a salicylate.
  • Salicylates include by are not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.
  • the anti-inflammatory agent may also be a corticosteroid.
  • the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.
  • the anti-inflammatory agent is a gold compound such as gold sodium thiomalate or auranofin.
  • the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.
  • a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.
  • Therapeutic agents can also include agents for pain and inflammation such as histamine and histamine antagonists, bradykinin and bradykinin antagonists, 5- hydroxytryptamine (serotonin), lipid substances that are generated by biotransformation of the products of the selective hydrolysis of membrane phospholipids, eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatory agents, analgesic-antipyretic agents, agents that inhibit the synthesis of prostaglandins and thromboxanes, selective inhibitors of the inducible cyclooxygenase, selective inhibitors of the inducible cyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin, cytokines that mediate interactions involved in humoral and cellular immune responses, lipid-derived autacoids, eicosanoids, P-adrenergic agonists, ipratropium,
  • At least one anti-inflammatory compound is an anti-monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti- TNF alpha monoclonal antibody.
  • an anti-monoclonal antibody such as eculizumab or pexelizumab
  • TNF antagonist such as entanercept, or infliximab
  • Therapeutic agents used in combination with the compounds of Structure (I) can also include small molecule compounds that inhibit the activation of NLRP3 inflammasomes, such as MCC950, sulforaphane, iisoliquiritigenin, P-hydroxybutyrate, flufenamic acid, mefenamic acid, 3,4-methylenedioxy-P-nitrostyrene (MNS), and parthenolide.
  • MCC950 small molecule compounds that inhibit the activation of NLRP3 inflammasomes
  • sulforaphane such as sulforaphane, iisoliquiritigenin, P-hydroxybutyrate, flufenamic acid, mefenamic acid, 3,4-methylenedioxy-P-nitrostyrene (MNS), and parthenolide.
  • MNS 3,4-methylenedioxy-P-nitrostyrene
  • Still other embodiments of the disclosure pertain to combinations in which at least one active agent is an immunosuppressant compound such as an immunosuppressant compound chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and my cophenolate mofetil.
  • an immunosuppressant compound such as an immunosuppressant compound chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and my cophenolate mofetil.
  • anticancer agent relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer.
  • Alkylating agents such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH- 3024, VAL-0834;
  • Platinum Compounds such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;
  • DNA altering agents such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine;
  • Topoisomerase Inhibitors such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin;
  • Microtubule modifiers such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel;
  • Antimetabolites such as asparaginase, azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur, trimetrexate;
  • Anticancer antibiotics such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;
  • Hormones/ Antagonists such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide;
  • Aromatase inhibitors such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane; Small molecule kinase inhibitors: such as cnzotimb, dasatimb, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib
  • medicaments which are administered in conjunction with the compounds described herein include any suitable drugs usefully delivered by inhalation for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti-infectives, e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines or pentamidine; antihistamines, e.g. methapyrilene; antiinflammatories, e.g.
  • analgesics e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine
  • anginal preparations e.g. diltiazem
  • antiallergics e.g. cromog
  • ephedrine adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5-dichloro-a-[[[6-[2- (2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate,
  • the medicaments are used in the form of salts (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament.
  • salts e.g., as alkali metal or amine salts or as acid addition salts
  • esters e.g., lower alkyl esters
  • solvates e.g., hydrates
  • the agents disclosed herein or other suitable agents are administered depending on the condition being treated.
  • the one or more compounds of the disclosure will be co-administered with other agents as described above.
  • the compounds described herein are administered with the second agent simultaneously or separately.
  • This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described above can be formulated together in the same dosage form and administered simultaneously.
  • a compound of the disclosure and any of the agents described above can be simultaneously administered, wherein both the agents are present in separate formulations.
  • a compound of the present disclosure can be administered just followed by and any of the agents described above, or vice versa.
  • a compound of the disclosure and any of the agents described above are administered a few minutes apart, or a few hours apart, or a few days apart.
  • the compounds of Structure (I) are administered as a mono-therapy.
  • a signal transduction or a mechanistic pathway For identification of a signal transduction or a mechanistic pathway and for detection of interactions between various signal transduction pathways, various scientists have developed suitable models or model systems, for example cell culture models and models of transgenic animals. For the determination of certain stages in the signal transduction cascade, interacting compounds can be utilized in order to modulate the signal.
  • the compounds of embodiments of the disclosure can also be used as reagents for testing NEK7-dependent signal transduction pathways in animals and/or cell culture models or in the clinical diseases mentioned in this application.
  • the methods of embodiments of embodiments of the disclosure can be performed either in vitro or in vivo.
  • the susceptibility of a particular cell to treatment with the compounds of Structure (I) can be particularly determined by in vitro tests, whether in the course of research or clinical application.
  • a culture of the cell is combined with a compound at various concentrations for a period of time which is sufficient to allow the active agents to inhibit NEK7 activity, usually between about one hour and one week.
  • In-vitro treatment can be carried out using cultivated cells from a biopsy sample or cell line.
  • the IC50 of the compounds of Structure (I) to inhibit NEK7 was determined by the concentration of the compound required to inhibit 50% of the activity of the NEK7 kinase.
  • the compounds of Structure (I) exhibited potency values of IC50 of less than about 5 mM, preferably less than about 1 mM and even more preferably less than about 0.100 mM as described in further detail in the Examples.
  • Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), qt (quintuplet) or brs (broad singlet).
  • starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or prepared as described herein.
  • TERT-BUTYL (2-FLUORO-4-HYDROXYPHENYL)CARBAMATE di -Tert-butyl dicarbonate (5.67 g, 26.0 mmol) was added to 4-amino-3 -fluorophenol (3.00 g, 23.6 mmol) and indium (III) chloride (0.052 g, 0.236 mmol) in DCM (30 mL) and the resulting mixture was stirred at 40 °C for 3 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 x 10 mL).
  • TERT-BUTYL (4-((3 -CHLORO- 1 -((2-(TRIMETHYLSILYL)ETHOXY)METHYL)- ///- PYRROLO[2,3-B]PYRIDIN-4-YL)OXY)-2-FLUOROPHENYL)CARBAMATE
  • NCS (0.792 g, 5.93 mmol) was added to a solution of tert-butyl (2-fluoro-4-((l-((2- (trimethylsilyl)ethoxy)methyl)-7J/-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)phenyl)carbamate (Cl, 2.700 g, 5.70 mmol) in acetonitrile (30 mL) and the resulting mixture was stirred at 60 °C overnight. Following completion of the reaction (as indicated by UPLC), the reaction mixture was concentrated under reduced pressure to yield a residue which was taken in EtOAc (100 mL) and washed with brine (10 mL).
  • TERT-BUTYL (4-((3 -CYCLOPROPYL- 1 -((2-(TRIMETHYLSILYL)ETHOXY)METHYL)-777-
  • Step 1 Synthesis of tert-butyl (4-((3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-777- pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2-fluorophenyl)carbamate
  • NBS (0.217 g, 1.217 mmol) was added to a solution of tert-butyl (2-fluoro-4-((l-((2- (trimethylsilyl)ethoxy)methyl)-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)phenyl)carbamate (Cl, 0.524 g, 1.106 mmol) in DMF (7 mL) and the resulting mixture was stirred at 25 °C overnight. Following completion of the reaction (as indicated by UPLC), the reaction mixture was poured into crushed ice (70 g), stirred at 25 °C for 15 minutes, and extracted with EtOAc (3 x 50 mL).
  • Step 2 Synthesis of tert-butyl (4-((3-cyclopropyl-l-((2-(trimethylsilyl)ethoxy)methyl)- 777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2-fluorophenyl)carbamate
  • TERT-BUTYL (3 -FLUORO-4-(( 1 -((2-(TRIMETHYL SIL YL)ETHOXY)METHYL)- 1H- PYRROLO [2,3 -B]PYRIDIN-4-YL)OXY)PHENYL)CARB AMATE
  • TERT-BUTYL (4-((3 -CHLORO- 1 -((2-(TRIMETHYLSILYL)ETHOXY)METHYL)- 1H- PYRROLO [2,3 -B]PYRIDIN-4-YL)OXY)-2,6-DIFLUOROPHENYL)CARB AMATE
  • TERT-BUTYL (4-((l -((2-(TRIMETHYLSILYL)ETHOXY)METHYL)-///-PYRROLO[2,3- B]PYRIDIN-4-YL)OXY)CYCLOHEXYL)CARBAMATE
  • Step 1 Synthesis 4-((/ ⁇ /7-butoxycarbonyl)amino)cyclohexyl 4-methylbenzenesulfonate:
  • Step 2 Synthesis of tert-butyl (4-((l/7-pyrrolo[2,3-Z>]pyridin-4- yl)oxy)cyclohexyl)carbamate
  • Step 3 tert-butyl (4-((l-((2-(trimethylsilyl)ethoxy)methyl)-7J/-pyrrolo[2,3-Z>]pyridin-4- yl)oxy)cyclohexyl)carbamate
  • DIPEA 0.042 ml, 0.241 mmol
  • SEM-C1 0.043 ml, 0.241 mmol
  • tert-butyl (4-(( l7/-pyrrolo[2,3-A]pyridin-4-yl)oxy)cyclohexyl)carbamate 0.080 g, 0.241 mmol
  • acetonitrile 5 mL
  • TERT-BUTYL (4-((3 -CHLORO- 1 -((2-(TRIMETHYLSILYL)ETHOXY)METHYL)- 1H- PYRROLO [2,3 -B]PYRIDIN-4-YL)OXY)CYCLOHEXYL)CARB AMATE
  • step 3 of intermediate, D8 The title compound was obtained following a similar procedure described for step 3 of intermediate, D8, starting from (4-((l-((2-(tri methyl silyl )ethoxy)methyl -lH- pyrrolo[2,3-Z>]pyridin-4-yl)oxy)cyclohexyl)carbamate (0.08 g, 0.173 mmol) and NCS (0.026 g), and was obtained as a yellow gum (0.08 g, 78% yield).
  • Step 1 Synthesis of 4-chloro-l-(phenylsulfonyl)-777-pyrrolo[2,3-Z>]pyridine
  • Step 2 Synthesis of 4-chloro-2-methyl-l-(phenylsulfonyl)-777-pyrrolo[2,3-Z>]pyridine
  • reaction mixture was quenched with a saturated NH4Q solution (15 mL) and extracted with EtOAc (2 x 30 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.0 g, 57% yield) as a pale yellow gum which was used without further purification.
  • Step 4 Synthesis of 4-chloro-2-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-777- pyrrolo[2,3-Z>]pyridine
  • step 3 of intermediate C9 The title compound was obtained following a similar procedure described for step 3 of intermediate C9, starting from 4-chloro-2-methyl-777-pyrrolo[2,3-Z>]pyridine (0.75 g, 4.50 mmol). DIPEA (1.455 mL, 8.10 mmol), and SEM-C1 (1.118 ml, 6.30 mmol), and was obtained as a pale yellow liquid (0.75 g, 53% yield).
  • Step 5 Synthesis of tert-butyl (2-fhioro-4-((2-methyl-l-((2-
  • TERT-BUTYL (4-((3-CHLORO-2-METHYL-l -((2 -(TRIMETHYL SILYL )ETHOXY)METHYL )-lH- PYRROLO[2,3-B]PYRIDIN-4-YL)OXY)-2-FLUOROPHENYL)CARBAMATE
  • Step 1 Synthesis of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-777-pyrrolo[2,3- d ]pyrimidine
  • Step 1 Synthesis of 4-(4-nitro-2-(trifluoromethyl)phenoxy)-777-pyrrolo[2,3-Z>]pyridine
  • Step 2 Synthesis of 4-(( 1H -pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-3-(trifluoromethyl)aniline
  • Iron powder (1.20 g, 21.65 mmol) and ammonium chloride (1.15 g, 21.65 mmol) were added to a solution of 4-(4-nitro-2-(trifluoromethyl)phenoxy)- 1H -pyrrolo[2,3-Z>]pyridine (0.70 g, 2.165 mmol) in ethanol (20 mL) and water (8 mL) and the resulting suspension was stirred at 80 °C for 3 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad of celite which was then rinsed with EtOAc (2 x 15 mL).
  • reaction mixture was directly concentrated under reduced pressure to yield crude material which was purified by Isolera (silica gel 230-400 mesh, eluting with 3% EtOAc in petroleum ether) to yield the title compound as a colorless liquid (0.08 g, 54% yield).
  • NCS (0.075 g, 0.561 mmol) was added to a solution of 4-(2,5-difluoro-4-nitrophenoxy)- l-((2-(trimethylsilyl)ethoxy)methyl)-777-pyrrolo[2,3-Z>]pyridine (0.215 g, 0.510 mmol) in DMF (10 mL) and the resulting mixture was stirred at 25 °C for 12 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was poured into crushed ice (100 g) and extracted with DCM (2 x 25 mL).
  • Iron powder (0.388 g, 6.95 mmol) and ammonium chloride (0.372 g, 6.95 mmol) were added to a solution of 3-chloro-4-(2,5-difluoro-4-nitrophenoxy)-l-((2- (trimethylsilyl)ethoxy)methyl)-777-pyrrolo[2,3-Z>]pyridine (0.317 g, 0.695 mmol) in ethanol (5 mL) and water (2 mL) and the resulting suspension was stirred at 80 °C for 3 h. Following completion of the reaction (as indicated by TLC), the reaction mixture was filtered through a pad celite which was then rinsed with EtOAc (2 x 5 mL).
  • Step 5 Synthesis of 4-((3-chloro-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2,5- difluoroaniline
  • Step 1 Synthesis of tert-butyl (4-((2-amino-3-nitropyridin-4-yl)oxy)-2- fluorophenyl)carbamate
  • reaction mixture was diluted with EtOAc (10 mL) and washed with ice-cold water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield crude material which was purified by flash chromatography (silica gel 230-400 mesh, eluting with 30% EtOAc in petroleum ether), affording the title compound as an off white solid (0.326 g, 62 % yield).
  • Step 2 Synthesis of tert-butyl (4-((2,3-diaminopyridin-4-yl)oxy)-2- fluorophenyl)carbamate
  • step 4 of intermediate D8 The title compound was obtained following a similar procedure described for step 4 of intermediate D8, starting from tert-butyl (4-((2-amino-3-nitropyridin-4-yl)oxy)-2- fluorophenyl)carbamate (0.326 g, 0.895 mmol), iron powder (0.500 g, 8.950 mmol), and ammonium chloride (0.479 g, 8.950 mmol), and was obtained as an off-white solid (0.29 g) which was used without further purification.
  • Triethylamine (2.0 eq) was added to a mixture of amine intermediate (Dl-15, 1.0 eq) and carbamate intermediate (El-7, 1.0 eq) in THF (5 mL) and the resulting solution was heated to 60 °C for 12 h. Following completion of the reaction (as indicated by LC-MS), the reaction mixture was concentrated under reduced pressure to yield crude material which was purified by RP-HPLC, affording the title compounds.
  • the title compound was obtained following the general procedure described for example 1, starting from 4-((177-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-3-(trifluoromethyl)aniline (D6, 0.100 g, 0.34 mmol) and phenyl (3 -(tert-butyl)- l-phenyl-777-pyrazol-5-yl)carbamate (El, 0.114 g, 0.34 mmol), and was obtained as a reddish-brown solid (35 mg, 19% yield).
  • the title compound was obtained following the general procedure described for example 1, starting from 2-fluoro-4-((2-methyl-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)aniline (D12, 0.057 g, 0.22 mmol) and phenyl (3 -(tert-butyl)- l-phenyl-777-pyrazol-5-yl)carbamate (El, 0.074 g, 0.22 mmol), and was obtained as an off-white solid (7 mg, 6% yield).
  • the title compound was obtained following the general procedure described for example 1, starting from 4-((3-chloro-/7/-pyrrolo[2,3-b]pyridin-4-yl)oxy)-2-fluoroaniline (DI, 0.092 g, 0.33 mmol) and phenyl (3-(tert-butyl)-l-methyl-777-pyrazol-5-yl)carbamate (E2, 0.09 g, 0.33 mmol), and was obtained as an off-white solid (15 mg, 10% yield).
  • the title compound was obtained following the general procedure described for example 1, starting from 4-((3-chloro-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2,6-difluoroaniline (D7, 0.050 g, 0.16 mmol) and phenyl (3-(tert-butyl)-l-phenyl-777-pyrazol-5- yl)carbamate (El, 0.057 g, 0.16 mmol), and was obtained as an off-white solid (4.4 mg, 7% yield).
  • the title compound was obtained following the general procedure described for example 1, starting from 4-((3-chloro-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2-fluoroaniline (DI, 0.075 g, 0.27 mmol) and phenyl (l-(4-cyanophenyl)-3-methyl-777-pyrazol-5- yl)carbamate (E3, 0.086 g, 0.27 mmol), and was obtained as an off-white solid (18.7 mg, 14% yield).
  • the title compound was obtained following the general procedure described for example 1, starting from phenyl (4-((3-chloro-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2- fluorophenyl)carbamate (DI, 0.040 g, 0.144 mmol) and 3 -cyclopropyl- l-phenyl-777- pyrazol-5-amine (E5, 0.046 g, 0.144 mmol), and was obtained as an off-white solid (3 mg, 4% yield).
  • the title compound was obtained following the general procedure described for example 1, starting from 4-((3-chloro-2-methyl-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2- fluoroaniline (Dl l, 0.023 g, 0.079 mmol) and phenyl (3 -(tert-butyl)- l -phenyl-1H - pyrazol-5-yl)carbamate (El, 0.026 g, 0.079 mmol), and was obtained as an off-white solid (3 mg, 7% yield).
  • the title compound was obtained following the general procedure described for example 1, starting from 4-((3-chloro-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2-fluoroaniline (DI, 0.073 g, 0.263 mmol) and phenyl (l-phenyl-3-(l-(trifluoromethyl)cyclopropyl)-777- pyrazol-5-yl)carbamate (E6, 0.102 g, 0.263 mmol), and was obtained as an off-white solid (25.0 mg, 17% yield).
  • the title compound was obtained following the general procedure described for example 1, starting from 4-((3-chloro-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)cyclohexan-l-amine (D9, 0.035 g, 0.132 mmol) and phenyl (3-(TER-Tb-utyl)- l -phenyl-1H -pyrazol-5- yl)carbamate (El, 0.044 g, 0.132 mmol), and was obtained as an off-white solid (5.9 mg, 9% yield).
  • the title compound was obtained following the general procedure described for example 1, starting from 4-((3-chloro-777-pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2-fluoroaniline (DI, 0.078 g, 0.281 mmol) and phenyl (3 -(tert-butyl)- l-(l-m ethylpiperidin-4-yl)- 1H-pyrazol- 5-yl)carbamate (14H, 0.100 g, 0.281 mmol), and was obtained as an off-white solid (4.5 mg, 3% yield).
  • Step 1 Synthesis of N-(3-(tert-butyl)-l-phenyl-777-pyrazol-5-yl)-2-(2-fluoro-4- hydroxyphenyl)acetamide
  • Step 2 Synthesis of N-(3-(tert-butyl)-l-phenyl-777-pyrazol-5-yl)-2-(2-fluoro-4-((l-((2-)
  • step 3 of intermediate D8 The title compound was obtained following a similar procedure described for step 3 of intermediate D8, starting from N-(3-(tert-butyl)-l-phenyl-777-pyrazol-5-yl)-2-(2-fluoro- 4-((l-((2-(trimethylsilyl)ethoxy)methyl)-777-pyrrolo[2,3-Z>]pyridin-4- yl)oxy)phenyl)acetamide (0.040 g, 0.065 mmol) and NCS (0.008 g, 0.059 mmol), and was obtained as a yellow gum (0.04 g, 55% yield).
  • Step 4 Synthesis of N-(3-(tert-butyl)-l-phenyl-777-pyrazol-5-yl)-2-(4-((3-chloro-777- pyrrolo[2,3-Z>]pyridin-4-yl)oxy)-2-fluorophenyl)acetamide
  • Casein substrate from bovine milk, hydrolyzed and partially dephosphorylated mixture of a, P and K caseins, obtained from Sigma Aldrich, catalogue # C4765, diluted in distilled water to a final concentration of 1 mg/mL
  • full-length recombinant human NEK7 expressed by baculovirus in Sf9 insect cells using a N-terminal GST tag, obtained from SignalChem, catalogue # N09-10G, 0.1 pg/pL
  • assay buffer (20 mM Hepes pH 7.5, 10 mM MgCh, 1 mM EGTA, 0.02% Brij 35, 0.02 mg/ml BSA, 0.1 mM NasVCU, 2 mM DTT, 1% DMSO).
  • THP-1 cells were plated in each well of a 6-well TC plate and incubated with 40 nM PMA in RPMI (10% FBS, 1% Penstrep) for 24 hours. The media was then removed and cells were rested in RPMI (10% FBS, 1% Penstrep) for 24 hours after which time the media was removed and cells were pre-treated for 2 hours with various concentrations of compounds of interest (typically serial 3 -fold dilution in RPMI + 5% FBS, concentrations ranging from 1 pM to 0.5 nM) in RPMI (5% FBS).
  • concentrations of compounds of interest typically serial 3 -fold dilution in RPMI + 5% FBS, concentrations ranging from 1 pM to 0.5 nM
  • the media was again removed and cells were incubated with 250 ng/mL LPS and compounds of interest (concentrations as above) in RMPI (5% FBS) for 2 hours. The media was removed for a last time and cells were incubated with 20 pM nigericin and compounds of interest (concentrations as above) in Opti-MEM for 30 minutes. Cell media was then collected and the amount of cleaved IL-ip was determined using a JESS instrument (Protein Simple) and standard protocols. Cleaved Il-ip antibody was obtained from Cell Signaling (catalogue #83186S) and was used at 1 :20 dilution in antibody diluent 2. Protein Simple lx anti-Rabbit HRP secondary antibody was used along with Protein Simple luminol and peroxide for chemiluminescent detection. Primary antibody incubation time was increased from 30 minutes to 60 minutes.
  • IC50 range from 301 - 500 nM
  • IC50 range from 301 - 500 nM

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Abstract

L'invention concerne des composés ayant une activité en tant qu'inhibiteurs de NEK7. Les composés ont une structure (I) : ou un sel, stéréoisomère ou promédicament pharmaceutiquement acceptable de celui-ci, dans laquelle A, X, Y, Z, R1a, R1b, R2a, R2b, R3, et R4 sont tels que définis dans la description. L'invention concerne également des procédés associés à la préparation et à l'utilisation de tels composés, des compositions pharmaceutiques comprenant de tels composés et des procédés pour moduler l'activité de l'inflammation de NLRP3.
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WO2024059200A1 (fr) * 2022-09-14 2024-03-21 Halia Therapeutics, Inc. Inhibiteurs de nek7
US12091413B2 (en) 2020-05-08 2024-09-17 Halia Therapeutics, Inc. Inhibitors of NEK7 kinase

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WO2024059200A1 (fr) * 2022-09-14 2024-03-21 Halia Therapeutics, Inc. Inhibiteurs de nek7

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